NF-κB-inducing kinase controls lymphocyte and osteoclast activities in inflammatory arthritis

NF-kappa B is an important component of both autoimmunity and bone destruction in RA. NF-kappa B-inducing kinase (NIK) is a key mediator of the alternative arm of the NF-kappa B pathway, which is characterized by the nuclear translocation of Re1B/p52 complexes. Mice lacking functional NIK have no peripheral lymph nodes, defective B and T cells, and impaired receptor activator of NF-kappa B ligand-stimulated osteoclastogenesis. We investigated the role of NIK in murine models of inflammatory arthritis using Nik(-/-) mice. The serum transfer arthritis model is initiated by preformed antibodies and required only intact neutrophil and complement systems in recipients. While Nik(-/-) mice had inflammation equivalent to that of Nik(-/-) controls, they showed significantly less periarticular osteoclastogenesis and less bone erosion. In contrast, Nik(-/-) mice were completely resistant to antigen-induced arthritis (AIA), which requires intact antigen presentation and lymphocyte function but not lymph nodes. Additionally, transfer of Nik(-/-) splenocytes or T cells to Rag2(-/-) mice conferred susceptibility to AIA, while transfer of Nik(-/-) cells did not. Nik(-/-) mice were also resistant to a genetic, spontaneous form of arthritis, generated in mice expressing both the KRN T cell receptor and H-2(g7). Thus, NIK is important in the immune and bone-destructive components of inflammatory arthritis and represents a possible therapeutic target for these diseases.